PROJECT SUMMARY Since 1988, 154,944 living individuals in the US have donated a kidney. In 2018 alone, 6,446 living donor kidney transplants were performed in the US from a total of 16,313 transplants. To make informed decisions about kidney donation, living donors must be aware of potential risks associated with organ donation. The effects of kidney donation upon skeletal health are not well-defined. Living kidney donors may potentially have an increased risk of fractures due to reductions in renal mass and glomerular filtration rate (GFR) and concentrations of serum 1,25-dihydroxyvitamin D (1,25(OH)2D), and secondary increases in parathyroid hormone (PTH) and bone turnover. The scientific premise of our application is based on observations from a prospective study, in which we demonstrated that 6 and 36 months after donation, kidney donors had significantly higher serum (s) intact PTH and fibroblast growth factor-23 (FGF-23) concentrations, and reduced s1,25(OH)2D, phosphate (Pi) concentrations, and tubular Pi reabsorption compared to healthy controls. Higher concentrations of bone resorption and formation markers were observed in donors compared to healthy controls. Preliminary data from the Rochester Epidemiology Project show a 2-3-fold excess risk of fractures and a 3-fold excess risk of osteoporosis in individuals who had a nephrectomy compared to control subjects. The studies suggest that bone quality may be impaired in kidney donors predisposing them to fractures. We hypothesize that reductions in renal mass and GFR following kidney donation result in a decrease in s1,25(OH)2D and an increase in sPTH and sFGF-23 concentrations, which in turn contribute to increased bone turnover, reductions in bone density and strength and risk of fractures. To test our hypothesis, we propose two aims. In AIM 1, we will compare the risk of fractures among 3000 living kidney donors with the risk of fractures in a group of age-, sex-, race-, and comorbidity-matched subjects who would have been eligible to donate but did not donate a kidney. In AIM 2 we will assess skeletal health in 200 kidney donors who are ?10 years after kidney donation and are ?50 years of age by measuring areal bone mineral density at the lumbar spine, hip and forearm; skeletal architecture and strength by peripheral high-resolution micro-computed tomography and finite element analysis; and serum mineral and bone biomarkers. For comparison, we will examine 200 age-, sex-, race- and comorbidity-matched controls that have not donated a kidney, but would have been healthy enough to donate. Our studies will provide important, previously unavailable information, regarding the risk of fractures in a large cohort of kidney donors, and will identify mechanisms by which skeletal complications occur. An observed increase in fractures amongst kidney donors will change medical practice by supporting evaluation of abnormalities in mineral metabolism and skeletal integrity in donors. Therapy of disordered mineral metabolism with 1?-hydroxylated vitamin D analogs would be indicated. Conversely, demonstration of an absence of increased fractures amongst donors will reassure kidney donors of the safety of donation.